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On August 8, 2016, FDA issued two highly anticipated draft guidance documents, entitled Deciding When to Submit a 510(k) for a Change to an Existing Device1 (general guidance) and Deciding When to Submit a 510(k) for a Software Change to an Existing Device2 (software guidance). Both are intended to help device manufacturers determine whether a proposed change to a 510(k)-cleared device requires a new 510(k) clearance. The first applies broadly to all cleared devices, while the second focuses on software-specific considerations. Once finalized, the draft guidance documents will replace FDA's longstanding 1997 guidance on the same topic.3

I. Introduction and Historical Context

FDA's current policy for when a modification to an existing device requires a new 510(k) clearance was set forth in its 1997 Blue Book Memorandum (#K97-1). Although FDA previously tried to update the 1997 guidance in a July 2011 draft guidance; that draft met with strong backlash from industry, which perceived it as interpreting the regulatory requirements governing device changes in new and unduly stringent ways. The 2011 draft guidance was viewed as requiring 510(k) clearance for changes that industry believed had not required it in the past. Pressure from industry ultimately led Congress to require withdrawal of the 2011 draft guidance through enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012.

The new draft guidance documents incorporate input from FDA's 2013 public meeting on 510(k) device modifications and comments received in response to FDA's corresponding report to Congress in January 2014, which explained that the 2011 draft guidance was not intended to fundamentally change the policy reflected in the 1997 guidance. At that time, FDA announced that targeted revisions to the 1997 guidance to clarify key terms and decision-making guidelines would be forthcoming. The new draft guidances are FDA's effort to fulfill that promise.

The new draft guidances build on the framework established in the 1997 guidance and incorporate several new considerations that will affect 510(k) filing decisions. In direct response to industry feedback on the withdrawn 2011 guidance, the new guidances retain and build on the decision-making flowcharts from the 1997 guidance. The flowcharts have been updated significantly and include a number of new questions industry should ask in assessing changes. As a starting principle, the main flowchart requires the manufacturer to assess its intent for each change. While this may be a natural question to ask, it is not obviously reflective of the regulatory standard for such changes (whether they could significantly affect safety or effectiveness) and may be met with some pushback from industry. In addition, the guidance places a large focus on using risk management principles to evaluate specific device modifications. While this is something that FDA historically has expected companies to consider in documenting changes internally, such specific recommendations for this documentation have never before been articulated in guidance. Each flowchart includes a question regarding whether a risk assessment has identified any new or changed risks in the modified device as compared to the cleared version. This question appears to serve as a sort of "catch-all" category to capture risks that do not fall into any other category in the flowcharts. Thus, the addition of this question, as well as a number of other new questions in the individual flowcharts, has the potential to drive more new 510(k) submissions.

II. Overview of New Guidance Documents

A. General Principles

The general guidance starts out by articulating a number of principles that companies should bear in mind in assessing changes to 510(k)-cleared devices. While these principles are not new (some were previously stated in the 1997 guidance), and have been considered good practice for many years, they are things that have not always been well-understood by industry. Key principles include:

Both positive and negative impacts on safety or effectiveness can require a new 510(k).

Changes should be assessed separately as well as cumulatively (considering all changes made since 510(k) clearance).

All comparisons should be made to the version of the device most recently cleared by FDA, not the currently marketed product.4

A new 510(k) for a modified device should identify all changes that trigger the requirement for a new 510(k), and modifications that do not require a 510(k), including those implemented via memorandum to file (MTF) since the last clearance. Despite this, FDA offers the following advice regarding these types of situations:

If a change concerns a feature that would not typically be described in the original 510(k) for the device, it need not be listed in the new 510(k).

Changes that do not trigger the need for a new 510(k) may be immediately implemented, so long as this can be done independently of the changes that require FDA review.

Changes that are determined not to require a new 510(k) should be documented internally, in compliance with the Quality System Regulation.

B. Decision-Making Process

While the new draft guidances clearly build on the framework previously established in the 1997 guidance, they incorporate several new considerations that will affect the decision-making process overall and for each type of change.

As will be noted by industry, the flowcharts for decision-making have been updated significantly in the general guidance. Consistent with the 1997 policy, flowcharts are available for each type of change, including (1) labeling (including indications for use); (2) technology, engineering and performance5; and (3) materials. However, each flowchart includes two new questions which should be assessed:

Manufacturer's Intent: The new guidance indicates that the first question to ask in assessing whether a new 510(k) is needed for a change is whether the manufacturer intended the change to significantly affect device safety or effectiveness. While it is logical to consider the intent of the change, this threshold determination is new and is not explicitly required by the governing regulatory standard, which focuses on the impact of the change rather than what motivated it.

Risk Assessment: Manufacturers are to determine whether a risk assessment has identified any new or changed risks in the modified device as compared to the cleared version. This explicit focus on risk management is also new to the decision-making framework, and appears to serve as a sort of "catch-all" category to capture risks that do not fall into any other category in the flowcharts. Thus, this question has the potential to drive more new 510(k) submissions.

Regarding the risk assessment, the general guidance provides advice for using risk management principles to evaluate specific device modifications. FDA recommends that manufacturers use an accepted method of risk assessment, such as that established by ISO 14971. However, while ISO 14971 is focused on risks in terms of device safety, any risk assessment related to a device modification must also consider the impact on device efficacy since this is also a factor in determining whether a new 510(k) notice is necessary. In assessing whether a change significantly modifies the risks associated with a device, manufacturers should evaluate "the criticality of the device feature being modified to the safe and effective use of the device."

Other notable differences in the flowcharts from the 1997 guidance include:

Labeling flowchart

The new guidance asks whether it is a substantive change in indications for use (vs. does it affect the indications).

Changes to warnings/precautions and instructions for use (a new addition) are assessed in the context of whether they affect the indications for use.

Technology, engineering and performance flowchart

The guidance includes additional questions regarding cleaning, disinfection and sterilization, which is consistent with the agency's recent focus on issues of cross-contamination between patients in reusable medical devices.

For packaging or expiration date changes, the flowchart asks whether the protocol or method was included in the prior 510(k), in which case a new 510(k) is generally not required.

For design changes, the flowchart asks whether they "significantly affect the use" of the device. Under this question, in the text, the guidance discusses how changes to components or accessories could affect the device as a whole, and also emphasizes human factors considerations in assessing such changes.

Materials flowchart

In addition to material type, the new flowchart asks about changes in material processing.

The flowchart also considers whether the manufacturer has used that same material in other devices.

IVD flowchart

The flowchart drops the focus of the 1997 guidance on whether clinical data is needed to support the change in making the 510(k) decision, instead focusing on the results of the risk assessment and design V&V activities.

The general guidance also addresses the agency's interpretation of one of the more confusing parts of the regulations, which states that a 510(k) is required for a "major change or modification in the intended use of the device" (21 C.F.R. §807.81(a)(3)(ii)). Since the first criterion for substantial equivalence is that the modified device must have the same intended use as the predicate (21 C.F.R. §807.100(b)(1)), a major change or modification in the intended use would seem to render the modified device not substantially equivalent (NSE). FDA clarifies that if a device has a different intended use, it would be NSE, but that "labeling changes or modifications that have a major impact on intended use" would require a 510(k) under the guidance. In general, the focus should be on indications for use.

The new general guidance differs in some key ways from the withdrawn 2011 guidance:

Flowcharts / Decision-Making Framework: A major criticism of the 2011 guidance was that it omitted the flowcharts from the 1997 guidance. Many in industry relied on the flowcharts in making internal decisions regarding whether 510(k)s were required. The new guidance restores the flowcharts, while cautioning that they should be interpreted with the text. Note that while the 2011 guidance did not have flowcharts, it did list the questions manufacturers should ask in assessing device changes. Interestingly, while there were new/different questions in the 2011 guidance, the questions appeared to track more closely to the 1997 guidance than do the questions in the new draft guidance. In addition, the 2011 guidance provided examples underneath each question of what were perceived as new situations where a 510(k) would be needed, and was subsequently criticized as requiring more 510(k)s. The new draft general guidance includes a number of new questions not articulated in the 1997 guidance. The inclusion of these new questions could result in more 510(k)s, especially the general "catch all" risk assessment question, as noted above.

Manufacturing Changes: The new guidance does not include a section on manufacturing changes. This was a controversial part of the withdrawn 2011 guidance, especially since 510(k)s typically do not include manufacturing information. The new guidance has a paragraph on this topic, noting that manufacturers should assess the impact of manufacturing changes on labeling, technology/performance, or materials, and then use the appropriate flowchart.

C. Software-Specific Changes

The general guidance also reflects FDA's evaluation of new technologies that have gained in prominence since 1997, such as wireless communication. To thoroughly address these issues, the guidance is accompanied by a concurrently released draft guidance that focuses on changes to software in previously cleared medical devices. The draft software guidance is intended to operate in conjunction with the broader guidance discussed above and, accordingly, applies the same key principles, but presents a framework specific to assessing changes to software. The release of this software-specific guidance appears to reflect FDA's recognition that software modifications generate different types of considerations than other device modifications.6

Among the unique considerations addressed in the software-specific guidance are changes to address cybersecurity and changes that introduce a new cause, or modify an existing cause, of a hazardous situation. The agency cautions that the impact of software changes on safety and effectiveness is not always immediately apparent, such as with general code changes that are not intended to change device function but can, if not controlled properly, generate unexpected changes. The guidance also addresses the interaction between software and other device elements, for instance in considering whether a software change could affect performance specifications associated with a device's intended use. In parallel to the broader device-change draft guidance, the software guidance also reviews a number of examples of software changes and how they might be assessed per the decision-making framework set forth in the guidance.

D. Internal Documentation

Finally, the new general guidance further clarifies the process for documenting changes in a company's design file where the company has made a determination that its device modification(s) do not require submission of a new 510(k) notice. The strategy described is consistent with FDA's historical approach, but represents the first time this has been formally laid out in agency guidance. The guidance essentially provides a template for documenting these decisions (typically referred to as a letter to file (LTF) or memorandum to file (MTF)). Among the key points raised is that only highlighting the flowcharts provided in the guidance, or simply answering "yes" or "no" to each question without more details, is insufficient; documentation should include robust justification for the decision that a new 510(k) is not required. The guidance also provides a specific template for companies to use in documenting any such changes that the company determines do not require a new 510(k) notice.

III. Conclusion

Overall, the general framework provided in the recently issued guidance documents to guide manufacturers' assessment of whether a change requires a new 510(k) is similar to that set forth in the 1997 guidance. However, the new guidances provide numerous examples of the types of changes in each category (labeling, technology, materials, software) that would likely require a new 510(k) notice, along with additional explanation of relevant factors and outlines of how the agency would approach the various change assessments, to clarify FDA's thinking in this area.7

Specifically, the flowcharts for decision-making have been updated significantly and include a number of new questions for industry in assessing changes to their devices. In particular, the guidance documents both placed an emphasis on using risk management principles to evaluate device modifications and includes a question regarding new or changed risks in the modified device that appears to serve as a "catch-all" category to capture risks that do not fall into any other category in the flowcharts. This question, along with a number of additional questions manufacturers must consider in the individual flowcharts, has the potential to drive more new 510(k) submissions. The draft guidance documents are open for public comment until November 7, 2016; comments should be submitted to docket number FDA-2016-D-2021 for the general guidance and to docket number FDA-2011-D-0453 for the software guidance. In addition, FDA will hold a webinar to discuss these documents on August 25, 2016. Webinar details can be found at the following link: http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm514808.htm

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